There are three known subtypes of vasopressin receptors, V1a, V1b and V2. The V1b receptor is also known as the V3 receptor and the V1a receptor is also known as the V1 receptor. Each subtype has a distinct pattern of expression in tissues, with V2 found primarily in the kidney, where it mediates the antidiuretic activity of the endogenous ligand vasopressin (Favory et al, 2009). V1b is widely distributed in the brain (Hernando et al., 2001). V1a is found in a variety of tissues, including smooth muscle, liver, kidney, platelets, spleen and brain (Zingg, 1996; Ostrowski et al., 1994).
Agonists of the V2 receptor are clinically useful. Desmopressin is a V2 receptor agonist that is approved in some territories for treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders including haemophilia A and von Willebrand's disease. Desmopressin binds and activates both the V2 and V1b receptors, with weaker activity on the V1a.
Desmopressin has been shown to be partly excreted via the kidneys (e.g. Fjellestad-Paulsen et al., 1993), and the half-life of desmopressin is increased in patients with renal impairment (Ruzicka, et al. 2003; Agersoe et al. 2004). Agersoe et al. suggest that the increased half-life might lead to prolonged antidiuretic effects and increase the risk of hyponatremia, a drop in serum sodium levels that can lead to adverse events such as seizures or coma. They further state that “although desmopressin appears to be safe and well-tolerated by patients with impaired renal function, great caution should be exercised when titrating towards an efficient dosing regimen, if patients with moderately or severe renal function are to be treated with desmopressin at all.”
Therefore, there is a need for additional V2 receptor agonists with reduced activity at the V1b receptor. Additionally, V2 receptor agonists that do not rely as heavily on the kidneys for elimination may also be desirable.